Our objective is to understand those defects in the development of the immune system that lead to autoimmune insulin-dependent diabetes mellitus (IDDM). Our belief is that progress towards that goal can be obtained through study of the spontaneously diabetic BB rat. IDDM in BB rats is known to be a T cell dependent process. We hypothesize that the T cell abnormalities which predispose BB rats to diabetes arise from defects in the development of prothymocytes or their subsequent differentiation in the thymus. Specifically, we believe that there exist two T cell developmental defects in the diabetes prone (DP) BB rat and one in the coisogenic diabetes resistant (DR) BB rat. The first developmental defect leads to the generation of autoreactive, diabetogenic effector cells in both DP and DR animals; the second impairs the generation of RT6+ regulatory T cells only in DP rats. This proposal outlines experiments designed to provide understanding of the developmental basis of these defects. Our analysis suggests that the relative balance between effector and regulatory T cell populations modulates the predisposition of an animal to IDDM and may provide a paradigm for understanding autoimmunity in general. Specific Aim No. 1 is to investigate the cellular, biochemical, and molecular basis for the failure of RT6+ regulatory cells to develop in DP rats. Our plan is to study the development and differentiation of immunoregulatory cells in the DR rat and the basis for their deficiency in DP animals. Specific Aim No. 2 is to determine if defective development of RT6+ T cells leads to deficiencies in soluble factors that are important in immunoregulation. This work will focus both on the cytokine profile of regulatory RT6+ T cells during development and on the newly described soluble RT6 protein. Specific Aim No. 3 is to investigate the factors that predispose to the development of diabetogenic effector T cells in BB rats. The proposed experiments will analyze the development and phenotype of intrathymic and peripheral effector T cells. Particular attention will be focused on newly described defects in tolerance induction in BB rats and on morphological evidence for thymic epithelial abnormalities. The results of these studies should define the T cell developmental defects that predispose to autoimmune IDDM in BB rats. We hope that an understanding of these defects will eventually translate into the design of rational strategies for the prevention of human juvenile diabetes.